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Background: Electronic health record-linked portals may improve health-care quality for patients with cancer. Barriers to portal access and use undermine interventions that rely on portals to reduce cancer care disparities. This study examined portal access and persistence of portal use and associations with patient and structural factors before the implementation of 3 portal-based interventions within the Improving the Management of symPtoms during And following Cancer Treatment (IMPACT) Consortium., Methods: Portal use data were extracted from electronic health records for the 12 months preceding intervention implementation. Sociodemographic factors, mode of accessing portals (web vs mobile), and number of clinical encounters before intervention implementation were also extracted. Rurality was derived using rural-urban commuting area codes. Broadband access was estimated using the 2015-2019 American Community Survey. Multiple logistic regression models tested the associations of these factors with portal access (ever accessed or never accessed) and persistence of portal use (accessed the portal ≤20 weeks vs ≥21 weeks in the 35-week study period)., Results: Of 28 942 eligible patients, 10 061 (35%) never accessed the portal. Male sex, membership in a racial and ethnic minority group, rural dwelling, not working, and limited broadband access were associated with lower odds of portal access. Younger age and more clinical encounters were associated with higher odds of portal access. Of those with portal access, 25% were persistent users. Using multiple modalities for portal access, being middle-aged, and having more clinical encounters were associated with persistent portal use., Conclusion: Patient and structural factors affect portal access and use and may exacerbate disparities in electronic health record-based cancer symptom surveillance and management., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: Our aim was to describe the risk factors known to be related to sudden unexpected death in epilepsy (SUDEP) that can be extracted from patients that utilizes an online seizure diary tool (SeizureTracker™)., Method: We conducted a descriptive analysis of SeizureTracker™ users across factors relevant to SUDEP risk. We also compared our app-using cohort to published SUDEP case-control studies., Results: We report across seven risk factors from 30,813 users of SeizureTracker™ who had a median length of time using the app of 5.69 years (range from 1 month to 15 years). We found that they are at greater risk for SUDEP than groups from published studies (p < .00001) based on the risk factor of generalized tonic-clonic seizures., Significance: We demonstrated that the population using the SeizureTracker™ tool can be a valuable population for expanding investigation of SUDEP risk factors and is a first step towards establishing a large sample with a method to ascertain data prospectively that might be critical to developing a SUDEP risk algorithm., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Hydroxyurea reduces pain crises, acute chest syndrome, and blood transfusions in sickle cell disease (SCD), but potential detrimental effects on fertility and birth outcomes impede its use. Data on the effects of hydroxyurea taken for SCD during conception and pregnancy are scarce. The Sickle Cell Disease Implementation Consortium collected self-reported pregnancy history, corresponding hydroxyurea use, and pregnancy outcomes in women with SCD in the clinical setting. Among 1285 women 18-45 years of age, 737 (57.4%) reported 1788 pregnancies (1079 live births, 394 miscarriages, 40 stillbirths, 207 abortions, 48 current pregnancies, and 20 missing outcomes) of which 241 (15.9%) live births, miscarriages or stillbirths were conceived while on hydroxyurea. In univariate analyses, pregnancy number more than three, severe sickle genotype, history of stillbirth or miscarriage, and chronic kidney disease at enrollment were covariates significantly associated with a pregnancy ending in miscarriage or stillbirth. After adjustment for covariates and additional SCD severity markers in multivariate analyses, hydroxyurea use during conception and pregnancy, but not during conception only, was associated with an increase in the odds ratio (OR) of miscarriage or stillbirth (OR 2.21, 95% confidence interval [CI] 1.40-3.47). In analyses of live birth outcomes, hydroxyurea use during conception and pregnancy was associated with birth weight < 5.5 pounds in full-term infants (OR 2.98, 95% CI 1.09-7.38) but not with prematurity or serious medical problems at birth. These findings suggest that hydroxyurea use may be safe up to the time of conception, but that clinicians should continue to advise caution regarding use during pregnancy., (© 2022 Wiley Periodicals LLC.)

Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging advances allow for early, even prenatal, detection. Genetic studies suggest mutations in GLI3 and other patterning genes are involved in HH pathogenesis. About 50%-80% of children with HH have severe rage and aggression and a majority of patients exhibit externalizing disorders. Behavioral disruption and intellectual disability may predate epilepsy. Neuropsychological, sleep, and endocrine disorders are typical. The purpose of this article is to provide a summary of the current understanding of HH and to highlight opportunities for future research., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: We evaluated a multi-parametric approach to seizure detection using cardiac and activity features to detect a wide range of seizures across different people using the same model., Methods: Electrocardiogram (ECG) and accelerometer data were collected from a chest-worn sensor from 62 children aged 2-17 years undergoing video-electroencephalogram monitoring for clinical care. ECG data from 5 adults aged 31-48 years who experienced focal seizures were also analyzed from the PhysioNet database. A detection algorithm was developed based on a combination of multiple heart rhythm and motion parameters., Results: Excluding patients with multiple seizures per hour and myoclonic jerks, 25 seizures were captured from 18 children. Using cardiac parameters only, 11/12 generalized seizures with clonic or tonic activity were detected as well as 7/13 focal seizures without generalization. Separately, cardiac parameters were evaluated using electrocardiogram data from 10 complex partial seizures in the PhysioNet database of which 7 were detected. False alarms averaged one per day. Movement-based parameters did not identify any seizures missed by cardiac parameters, but did improve detection time for 4 of the generalized seizures., Conclusion: Our data suggest that cardiac measures can detect seizures with bilateral motor features with high sensitivity, while detection of focal seizures depends on seizure duration and localization and may require customization of parameter thresholds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To test whether children with epilepsy have impairments in myocardial mechanics compared to controls without epilepsy., Methods: Children with refractory epilepsy with epilepsy duration of at least 3 years underwent echocardiography including conventional measurements and speckle tracking to assess longitudinal and circumferential strain. Parent-completed surveys, capturing critical aspects of the children's seizure history and cardiac risk factors, complemented retrospective chart reviews, which also included antiepileptic drug history. Normal echocardiograms from controls, matched for age and gender, were obtained from our institutional database and evaluated for strain., Results: Forty-one patients (median age = 10 years, interquartile range [IQR] = 5-15; 58.5% male) were enrolled. Epilepsy etiology included genetic (n = 26), structural (n = 6), genetic and structural (n = 5), infection (n = 3), and unknown (n = 1). No cardiac structural abnormalities were identified. Both longitudinal and circumferential strain were impaired (P < .03) in patients compared to controls (median [IQR] = 22.7% [21.2-24.2] vs 23.6% [22.2-26.1] and 22.0% [20.3-25.4] vs 24.5% [22.3-27.0], respectively), indicating decreased myocardial deformation/contraction. Shortening fraction was higher in patients (37.6% [35.7-39.7] vs 34.9% [32.5-38.7], P = .009); mitral valve E wave inflow velocity (84.8 cm/s [78.4-92.8] vs 97.2 cm/s [85.9-105.8], P = .005) and tissue Doppler lateral E' wave (13.9 cm/s [12.3-16.1] vs 17.3 cm/s [15.4-18.5], P < .001) were decreased compared to controls. Findings were similar in the pairs with epilepsy patients distinguished by the ability to independently ambulate. There was no difference between patients and controls in ejection fraction. Among the epilepsy patients, there were no associations between cardiac measurements and epilepsy characteristics, including seizure type and frequency and cardiotoxic antiseizure medication exposure after correction for multiple comparisons., Significance: Children with refractory epilepsy had impaired systolic ventricular strain compared to controls, not correlated with epilepsy history. Further studies are needed to determine the significance of these changes., (© 2020 International League Against Epilepsy.)

Objective: To evaluate the impact of pediatric sleep disturbances and night-time seizure monitoring of children with rare epilepsy syndromes on the sleep quality and mental health of caregivers., Study Design: A cross-sectional study was conducted using caregiver entered data from the Rare Epilepsy Network on pediatric sleep disturbances and Patient Reported Outcomes Measurement Information System measures for caregiver fatigue, sleep disturbance, sleep-related impairment, depression, anxiety, companionship, and cognition. Logistic regression was used to examine associations between risk factors and caregiver sleep quality., Results: Non-Hispanic white mothers comprised 83% of the 742 respondents in this study. After adjusting for covariates, difficulty falling asleep, excessive daytime sleepiness, frequent night-time awakenings, and very restless sleep in children were associated with fatigue (aOR 95% CI, 1.5-2.2), sleep-related disturbance (aOR 95% CI, 1.7-2.6) and sleep impairment (aOR 95% CI, 1.5-2.4) in caregivers. Caregiver anxiety (aOR 95% CI, 3.6-6.0) and depression (aOR 95% CI, 2.8-6.0) were also highly associated with their fatigue and sleep quality, whereas companionship (aOR 95% CI, 0.3-0.4) and higher caregiver cognition (aOR 95% CI, 0.1-0.2) were protective. In addition, sharing a room or bed or using methods that require listening for seizures were significantly related to sleep disturbance and fatigue in the caregivers., Conclusions: In rare epilepsies, pediatric sleep disturbances and night-time seizure monitoring are significantly associated with caregiver fatigue and poor sleep quality. In addition to the intense caregiving needs of children with rare epilepsies, fatigue and poor sleep quality in caregivers may contribute to or result from mental health problems., (© 2020 Published by Elsevier Inc.)

Several American Academy of Neurology (AAN) epilepsy practice guidelines recommend conversations that neurologists should have with patients and their parents. We sought to determine whether parents of pediatric patients with epilepsy had knowledge of epilepsy quality measures (EQMs) and whether they recalled having discussions with their child's neurologist about each of the EQM. Surveys were distributed to parents at five clinic sites associated with epilepsy centers in Washington, DC and Charlottesville, Virginia. Key questions on the parent survey included whether neurologists had discussed, or parents had knowledge of, EQM topics which included medication side effects, safety, reproductive health, transition to adult care, learning and attention problems, bone health, sudden unexpected death in epilepsy (SUDEP), and risk of epilepsy-related death. No data were collected from the neurologist or the medical record about EQM discussions. Among 233 completed surveys, parental knowledge and neurologist discussion of EQM were highly correlated (p < .00001). Epilepsy quality measures most discussed with high parental knowledge were medication side effects, safety, learning and attention problems, and bone health. Sudden unexpected death in epilepsy was least discussed and known. We found consistent care practices in adherence to EQM across settings from urban to rural communities, with patients of all ages and epilepsy severities and staffed by neurologists with various levels of epilepsy expertise. Despite reported high rates of adherence on several measures, we identified opportunities for improvement. Querying and counseling about EQM should be an ongoing conversation which evolves with the child's age and epilepsy-associated risks., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: To assess parental perspectives of the impact of epilepsy and seizures on siblings of children in the Seizures and Outcomes Study., Methods: Parents completed surveys about their child with epilepsy, their own health and well-being, and the impact of epilepsy on unaffected siblings., Results: The most common parental responses about the sibling were witnessing a seizure, protectiveness of the child with epilepsy, worry about seizures, belief that seizures cause pain, and pride toward the child with epilepsy. Embarrassment and keeping epilepsy a secret were rare. Parent reports supported that siblings that worried were more likely to have witnessed a seizure, feel sad or angry, think seizures cause pain, and have a parent with anxiety disorder., Discussion: Some siblings of children with epilepsy are at risk for psychosocial problems. Primary and specialty care providers are well positioned to identify and monitor these children through evaluations and referrals as necessary., (Copyright © 2017 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

Background: Unicuspid aortic valve (UAV) is a rare disorder, often difficult to distinguish from bicuspid aortic valve (BAV). BAV and UAV share valve pathology such as the presence of a raphe, leaflet fusion, aortic stenosis, aortic regurgitation, and/or ascending aortic dilatation, but a comprehensive echocardiographic comparison of patients with UAV and BAV has not been previously performed., Methods: We investigated UAV and BAV patients at an early stage of disease included in GenTAC, a national registry of genetically related aortic aneurysms and associated cardiac conditions. Clinical and echocardiographic data from the GenTAC Registry were compared between 17 patients with UAV and 17 matched-controls with BAV., Results: Baseline characteristics including demographics, clinical findings including family history of BAV and aortic aneurysm/coarctation, and echocardiographic variables were similar between BAV and UAV patients; aortic stenosis was more common and more severe in patients with UAV. This was evidenced by higher mean and peak gradient, smaller aortic valve area, and more advanced valvular degeneration (all P < .05). There were no significant differences in aortic dimensions, with a similar pattern of enlargement of the ascending aorta., Conclusions: The similar baseline characteristics with more accelerated aortic valve degeneration and stenosis suggest that UAV represents an extreme in the spectrum of BAV syndromes. Therefore, it is reasonable to consider application of recommendations for the management of patients with BAV to those with the rarer UAV., (© 2017 Wiley Periodicals, Inc.)

A survey of 146 pediatric care providers (PCPs) revealed that 75.3% were unaware that children with epilepsy were at risk of death, specifically from sudden unexpected (or unexplained) death in epilepsy (SUDEP). PCPs assume that the treating neurologist discusses these risks. Increasing PCPs' knowledge of SUDEP will help address the care gap related to informing families about SUDEP., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Previous small studies suggested reduced quality of life (QOL) for people with Marfan syndrome (MFS) compared with those without MFS. The national registry of GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) is a longitudinal observational cohort study of patients with conditions that predispose to thoracic aortic aneurysms and dissections, including MFS. At the time of registry enrollment, GenTAC study participants are asked to complete questionnaires about demographics, medical history, health habits, and QOL., Objectives: This study assessed QOL in GenTAC participants with MFS and identify associated factors using self-reported data., Methods: QOL was assessed using the 4 subscales of the Physical Component Summary (PCS) of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36): physical functioning; role limitations due to physical health; bodily pain; and general health. We studied the association of QOL with self-reported demographics, health behaviors, physical impairments, surgeries, comorbid medical conditions, medications, and MFS severity., Results: In the GenTAC registry, 389 adults with MFS completed the SF-36. Mean age was 41 years, 51% were men, 92% were white, and 65% were college graduates. The mean PCS composite score was 42.3. In bivariate analysis, predictors of better QOL included college education, marital status, higher household income, private health insurance, full-time employment, moderate alcohol use, fewer prior surgeries, fewer comorbid conditions, absence of depression, and less severe MFS manifestations. In a multivariable analysis, insurance status and employment remained significant predictors of QOL., Conclusions: In a large cohort of patients with MFS in the GenTAC registry, health-related QOL was below the population norm. Better QOL was independently associated with socioeconomic factors, not factors related to general health or MFS severity., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Self-reported epilepsy may be influenced by culture, knowledge, and beliefs. We screened 6420 residents of the District of Columbia (DC) for epilepsy to investigate whether socio-demographics were associated with whether they reported their diagnosis as epilepsy or as seizure disorder. Lifetime and active prevalence rates were 0.54% and 0.21%, respectively for 'epilepsy' and 1.30% and 0.70%, respectively for 'seizure disorder'. Seizure disorder was reported significantly more often than epilepsy among blacks, females, respondents≥50years, those with lower level education, respondents who lived alone and in low income neighborhoods, and those who resided in DC for at least five years. Clinicians should assure that patients and caregivers understand that epilepsy is synonymous with seizure disorder and other culturally appropriate terms, in order to optimize compliance with treatment, disease management instructions, and utilization of other resources targeted at persons with epilepsy. Furthermore, education and awareness campaigns aimed at improving access-to-care, reducing stigma, and increasing awareness of adverse events, such as SUDEP, should include a more diverse definition of epilepsy in their messages., (Copyright © 2016 Elsevier Inc. All rights reserved.)

On April 21, 2015, the first SCN8A Encephalopathy Research Group convened in Washington, DC, to assess current research into clinical and pathogenic features of the disorder and prepare an agenda for future research collaborations. The group comprised clinical and basic scientists and representatives of patient advocacy groups. SCN8A encephalopathy is a rare disorder caused by de novo missense mutations of the sodium channel gene SCN8A, which encodes the neuronal sodium channel Nav 1.6. Since the initial description in 2012, approximately 140 affected individuals have been reported in publications or by SCN8A family groups. As a result, an understanding of the severe impact of SCN8A mutations is beginning to emerge. Defining a genetic epilepsy syndrome goes beyond identification of molecular etiology. Topics discussed at this meeting included (1) comparison between mutations of SCN8A and the SCN1A mutations in Dravet syndrome, (2) biophysical properties of the Nav 1.6 channel, (3) electrophysiologic effects of patient mutations on channel properties, (4) cell and animal models of SCN8A encephalopathy, (5) drug screening strategies, (6) the phenotypic spectrum of SCN8A encephalopathy, and (7) efforts to develop a bioregistry. A panel discussion of gaps in bioregistry, biobanking, and clinical outcomes data was followed by a planning session for improved integration of clinical and basic science research. Although SCN8A encephalopathy was identified only recently, there has been rapid progress in functional analysis and phenotypic classification. The focus is now shifting from identification of the underlying molecular cause to the development of strategies for drug screening and prioritized patient care., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Objectives: This study sought to evaluate variability in aortic measurements with multiple imaging modalities in clinical centers by comparing with a standardized measuring protocol implemented in a core laboratory., Background: In patients with aortic disease, imaging of thoracic aorta plays a major role in risk stratifying individuals for life-threatening complications and in determining timing of surgical intervention. However, standardization of the procedures for performance of aortic measurements is lacking., Methods: To characterize the diversity of methods used in clinical practice, we compared aortic measurements performed by echocardiography, computed tomography (CT), and magnetic resonance imaging (MRI) at the 6 GenTAC (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) clinical centers to those performed at the imaging core laboratory in 965 studies. Each center acquired and analyzed their images according to local protocols. The same images were subsequently analyzed blindly by the core laboratory, on the basis of a standardized protocol for all imaging modalities. Paired measurements from clinical centers and core laboratory were compared by mean of differences and intraclass correlation coefficient (ICC)., Results: For all segments of the ascending aorta, echocardiography showed a higher ICC (0.84 to 0.93) than CT (0.84) and MRI (0.82 to 0.90), with smaller mean of differences. MRI showed higher ICC for the arch and descending aorta (0.91 and 0.93). In a mixed adjusted model, the different imaging modalities and clinical centers were identified as sources of variability between clinical and core laboratory measurements, whereas age groups or diagnosis at enrollment were not., Conclusions: By comparing core laboratory with measurements from clinical centers, our study identified important sources of variability in aortic measurements. Furthermore, our findings with regard to CT and MRI suggest a need for imaging societies to work toward the development of unifying acquisition protocols and common measuring methods., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: Describe the characteristics of persons with epilepsy (PWEs) and caregivers that have or have not heard of sudden unexpected death in epilepsy (SUDEP) prior to completing a survey through the Internet or in the clinical setting., Methods: An online survey for adult PWEs and caregivers was solicited by e-mail and newsletter to Epilepsy Therapy Project members. A similar survey was implemented in a clinic setting of a community hospital. The survey asked about seizure characteristics, epilepsy management, fear of death, and familiarity with the term SUDEP. Respondents that never heard of SUDEP read a definition and responded to questions about their initial reactions., Results: Surveys from 1,392 PWEs and 611 caregivers recruited through an epilepsy Website and a clinic demonstrated that Internet respondents were much more likely to have heard about SUDEP than the clinic population (71.1% vs. 38.8%; p < 0.001), and caregivers of PWEs were more likely to have heard about SUDEP than PWEs (76.2% vs. 65.2%; p < 0.001). Prior awareness was related to an increased level of education, more severe and longer duration of epilepsy, and having an epileptologist as the primary care provider. Although most PWEs and caregivers reported feelings of fear, anxiety, and sadness after first hearing of SUDEP, they wanted to discuss it with their doctor. Persons with epilepsy, and especially their caregivers, often worry that the PWEs may die of epilepsy or seizures. This worry escalated with knowledge of SUDEP and increased epilepsy severity. Approximately half of PWEs and caregivers believed that knowledge about SUDEP would influence their epilepsy management., Significance: Our results may help epilepsy care providers determine when to facilitate a discussion about epilepsy-related mortality and SUDEP among patients and caregivers, and to educate those at high risk about the importance of seizure control as well as reduce fears about death in patients with well-controlled and nonconvulsive epilepsies., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Previous data suggest women are at increased risk of death from aortic dissection. Therefore, we analyzed data from the GenTAC registry, the NIH-sponsored program that collects information about individuals with genetically triggered thoracic aortic aneurysms and cardiovascular conditions. We performed cross-sectional analyses in adults with Marfan syndrome (MFS), familial thoracic aortic aneurysm or dissection (FTAAD), bicuspid aortic valve (BAV) with thoracic aortic aneurysm or dissection, and subjects under 50 years of age with thoracic aortic aneurysm or dissection (TAAD <50 years). Women comprised 32% of 1,449 subjects and were 21% of subjects with BAV, 34% with FTAAD, 22% with TAAD <50 years, and 47% with MFS. Thoracic aortic dissections occurred with equal gender frequency yet women with BAV had more extensive dissections. Aortic size was smaller in women but was similar after controlling for BSA. Age at operation for aortic valve dysfunction, aneurysm or dissection did not differ by gender. Multivariate analysis (adjusting for age, BSA, hypertension, study site, diabetes, and subgroup diagnoses) showed that women had fewer total aortic surgeries (OR = 0.65, P < 0.01) and were less likely to receive angiotensin converting enzyme inhibitors (ACEi; OR = 0.68, P < 0.05). As in BAV, other genetically triggered aortic diseases such as FTAAD and TAAD <50 are more common in males. In women, decreased prevalence of aortic operations and less treatment with ACEi may be due to their smaller absolute aortic diameters. Longitudinal studies are needed to determine if women are at higher risk for adverse events., (Copyright © 2013 Wiley Periodicals, Inc.)

We investigated social and demographic factors as they relate to prevalence and incidence of epilepsy in Washington, DC, a culturally diverse area. Probability-based sampling was used to select 20,000 households to complete a mailed epilepsy screening survey on all household members. Screened individuals with a history of epilepsy were sent a detailed case survey about seizures and treatment. Prevalence and incidence of epilepsy were estimated using weighted data. Lifetime prevalence was 1.53% overall; 0.77% in Whites, 2.13% in Blacks, and 3.4% in those with less than a high school diploma. Prevalence of active epilepsy was 0.79% and followed similar subgroup comparisons as lifetime prevalence. Age-adjusted lifetime and active epilepsy from multivariate analyses demonstrated significantly higher rates for Blacks compared to Whites and for those not completing high school compared to those that attended graduate school. The incidence of epilepsy was 71 per 100,000 persons. Adults with active epilepsy were significantly less likely to live alone than those without epilepsy. Residents of DC for <4 years had the lowest prevalence and incidence of all subgroups indicating a possible healthy mover effect. This is the first study to provide estimates and profiles of the epilepsy population in DC which can help better target resources to improve the health and outcomes of people with epilepsy and their families., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: Patients with Marfan syndrome with aortic root aneurysms undergo elective aortic root replacement to avoid the life-threatening outcomes of aortic dissection and emergency repair. The long-term implications of failed aortic surveillance leading to acute dissection and emergency repair are poorly defined. We compared the long-term clinical courses of patients with Marfan syndrome who survive emergency versus elective proximal aortic surgery., Methods: The Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Registry is a National Institutes of Health-funded multicenter database and biorepository that enrolls patients with genetically triggered thoracic aortic aneurysms. Of the 635 patients with Marfan syndrome enrolled as of March 2011, 194 had undergone proximal aortic replacement. Patients were grouped according to emergency (n = 47) or elective (n = 147) status at the time of surgery., Results: Patients in the emergency group were more likely to have incomplete proximal aortic resection; 83% of emergency procedures included aortic root replacement, compared with 95% of elective procedures. At long-term follow-up (mean, >6 years), the emergency group had a higher incidence of chronic dissection of the distal aorta and significantly larger diameters in distal aortic segments than elective patients. Patients in the emergency group had undergone more operations (1.31 vs 1.11 procedures/patient; P = .01) and had lower activity scores on a health-related quality of life survey., Conclusions: For patients with Marfan syndrome, failed aortic surveillance and consequent emergency dissection repair have important long-term implications with regard to the status of the distal aorta, need for multiple procedures, and quality of life. These findings emphasize the importance of aortic surveillance and timely elective aortic root aneurysm repair for patients with Marfan syndrome., (Copyright © 2012 The American Association for Thoracic Surgery. All rights reserved.)

Background: Genetically triggered thoracic aortic conditions (GenTACs) represent an important problem for patients and their families. Accordingly, the National Heart, Lung, and Blood Institute established the first phase of its national GenTAC Registry in 2006., Enrollment and Diagnoses: Between 2007 and 2010, 6 enrolling centers established the GenTAC I Registry consisting of 2,046 patients (Marfan syndrome 576 [28.2%], bicuspid aortic valve disease 504 [24.6%], aneurysm or dissection age <50 years 369 [18%], and others). Biologic samples for DNA analyses (white blood cells or saliva) are available in 97%, and stored plasma is available in 60% of enrollees., Results: Initial scientific inquiry using the GenTAC Registry has included validation studies of genetic causes for aortic syndromes, potential usefulness of transforming growth factor beta (TGFB) blood levels in Marfan subjects, and current surgical approaches to ascending aortic conditions., Future Opportunity: The second phase of GenTAC will allow biannual follow-up of GenTAC I enrollees for up to 9 years, enrollment of an additional 1,500 subjects, further integration of imaging findings with clinical and genetic data through utilization of an imaging core laboratory, important validation of phenotype-genotype correlations through a phenotyping core laboratory, and integration of a scientific advisory committee to help define the full range and depth of the Registry's scientific capabilities. The registry resources are available to the external scientific community through an application process accessible at https://gentac.rti.org., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Background: For patients with thoracic aortic aneurysms (TAA), aortic size on imaging is widely used to guide clinical decision making. This study examined the impact of methodological variance on aortic quantification., Methods: We studied enrollees in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions. Aortic size on computed tomography was quantified by 2 linear methods; cross-sectional dimensions in axial (AX) and double oblique (DO) plane. Calculated area was compared to planimetry. Established cutoffs (area/height>10 cm2/m, diameter≥5 cm) for prophylactic TAA repair were used to compare surgical eligibility by each method., Results: Fifty subjects were studied. Aortic size differed between AX and DO at all locations (p≤0.001), with magnitude greatest at the sinotubular junction (4.8±1.1 vs 4.0±1.0 cm, p<0.001). The difference between AX and DO correlated with aortic angular displacement (r=0.37, p<0.01), which was threefold larger at the sinotubular junction (37±12 degrees) than the ascending aorta (12±5 degrees; p<0.001). At all locations, aortic area calculated using DO yielded smaller differences with planimetry than AX (p<0.05). DO and planimetry yielded equal prevalence (24%) of subjects eligible for prophylactic TAA repair based on area-height cutoff, whereas AX prevalence was higher (44%; p=0.006). Using a linear cutoff, AX yielded over a twofold greater prevalence of surgically eligible subjects (56%) than did DO (24%; p<0.001)., Conclusions: Established linear methods for aortic measurement yield different results that impact surgical eligibility. DO yielded improved agreement with planimetry and differed with AX in proportion to aortic geometric obliquity. Findings support DO measurements for imaging evaluation of subjects with TAA., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Genetic disorders are an important cause of thoracic aortic aneurysms (TAAs) in young patients. Despite advances in the treatment of genetically triggered TAAs, the optimal syndrome-specific treatment approach remains undefined. We used data from the National Institutes of Health-funded, multicenter National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) to characterize the contemporary surgical treatment of patients with genetically triggered TAAs., Methods: GenTAC's aim is to collect longitudinal clinical data and banked biospecimens from 2800 patients with genetically triggered TAAs. We analyzed data from the 606 patients (mean age, 37.5 years) enrolled in GenTAC to date whose clinical data were available., Results: The patients' primary diagnoses included Marfan syndrome (35.8%), bicuspid aortic valve with aneurysm (29.2%), and familial TAAs and dissections (10.7%). Of these, 56.4% had undergone at least one operation; the most common indications were aneurysm (85.7%), valve dysfunction (65.8%), and dissection (25.4%). Surgical procedures included replacement of the aortic root (50.6%), ascending aorta (64.8%), aortic arch (27.9%), and descending or thoracoabdominal aorta (12.4%). Syndrome-specific differences in age, indications for operation, and procedure type were identified., Conclusions: Patients with genetically transmitted TAAs evaluated in tertiary care centers frequently undergo surgical repair. Aneurysm repairs most commonly involve the aortic root and ascending aorta; distal repairs are less common. Like TAAs themselves, complications of TAAs, including dissection and aortic valve dysfunction, are important indications for intervention. Future studies will focus on syndrome- and gene-specific phenotypes, biomarkers, treatments, and outcomes to improve the treatment of patients with TAAs.

We sought to determine the incidence, prevalence, and life expectancy of Aicardi syndrome from 408 cases compiled from multiple international sources. Last known age ranged from less than 1 month to 42 years. The incidence rates per live births for the United States and The Netherlands were 1 per 105 000 and 1 per 93 000, respectively. The prevalence in the United States is greater than 853 cases, and the worldwide estimate is several thousand. Forty-five cases were deceased (age range, 1 month to 33 years), and the risk of death peaked at age 16. The probability of survival at 27 years of age was 0.62 (95% CI, 0.47-0.77). The risk of death by age follows other congenital neurological disorders with a wide range in severity of functional disability. The longer life expectancy found in our study hints at a higher functioning capacity in Aicardi syndrome and may inform counseling to families.

Background & Aims: Hemophilic siblings provide a unique population to explore the natural history of chronic hepatitis C., Methods: From 3993 hemophilic patients with hepatitis C, 257 sibling pairs, of which both members had evidence of hepatitis C infection, were studied to evaluate the genetic contribution to spontaneous and treatment-induced clearance of hepatitis C infection and progression of liver disease. Familial aggregation was assessed by comparing observed probabilities of concordance for these disease characteristics within sibling pairs to those expected for randomly paired hemophilic subjects. Additional measures of familial aggregation, heritability, and sibling relative risk were also calculated., Results: Among human immunodeficiency virus-negative subjects, concordance for spontaneous viral clearance was 2-fold higher in siblings compared with randomly paired subjects (8.8% vs 4.3%, respectively, P = .04). Similarly, the concordance rate for treatment-related viral clearance was over twice that among sibling pairs than among randomly paired hemophiliacs (31.3% vs 13.3%, respectively, P = ns). Heritability estimates for spontaneous and treatment-induced viral clearance were 0.24 +/- 0.14 (P = .04) and 0.43 +/- 0.42 (P = .10), respectively. The sibling relative risks for these respective characteristics were 1.6 and 1.7. Concordance for advanced liver disease was higher among siblings but did not reach statistical significance (4.0% vs 2.3%, respectively, P = ns). The heritability estimate was 0.29 +/- 0.13 (P = .02)., Conclusions: Concordance rates and heritability estimates for spontaneous and treatment-related viral clearance indicate that genetic factors have a modest influence on the outcome of hepatitis C, although shared environmental factors cannot be excluded. Investigations to map candidate disease-susceptibility genes associated with these characteristics must be approached with caution.

Liver biopsy plays a pivotal role in the management of patients with a variety of liver diseases, including chronic hepatitis C virus. The major risk of the procedure is the potential for significant haemorrhagic complications. Although the data are limited, the procedure does not appear to pose excessive risk to the patient with inherited disorders of coagulation, provided that adequate haemostasis can be achieved prior to the liver biopsy. This requires close coordination of care between the hepatologist and the haematologist. Indications for liver biopsy should be the same in patients with haemophilia as in other populations.

In this article, a comparative analysis of the data stemming from the studies conducted in the field of immune tolerance treatment (ITT) of hemophilia A was attempted. Comparisons are difficult because previous studies differ in many respects, including the dosage of factor (F) VIII, the number of FVIII administrations per day, the association with immunosuppressive drugs (prednisone, cyclophosphamide), and, most importantly, the definition of success in terms of the reacquisition of tolerance. However, a number of variables consistently influenced outcome: the inhibitor titer, either the maximum one or the one assayed before immune tolerance (IT) start and age. As to the FVIII dose, results are contrasting, even though the overall impression is that high dosages are associated with higher success rates. Treatment duration analyses appear to be fairly consistent in all the studies, with 1 year as the crucial time period useful in predicting outcome. Preliminary data suggest that concentrates containing von Willebrand factor may increase the success rate and allow patients refractory to IT procedures carried out with ultrapure or recombinant concentrates to become tolerant in the end. These data need to be formally confirmed in trials that compare the different brands. In the studies published so far, a common language and widely accepted definitions of the variables have emerged, which are important in setting up the controlled trials and improving the comparison among published data.

Many persons with hemophilia were infected with hepatitis C and B viruses (HCV, HBV) and HIV, but the consequences of these transfusion-acquired infections are poorly defined. We estimated the risk of HCV-related end-stage liver disease (ESLD) and the associations of age, HBV, and HIV with that risk. All 1816 HCV-seropositive hemophilic patients at 16 centers were followed for up to 16 years. Of these, 624 were HIV(-) and 1192 were HIV-coinfected; 135 had persistent HBV surface antigenemia, 1374 had resolved HBV infection, and 287 were HBV-uninfected. ESLD was defined as bleeding esophageal varices, hepatic encephalopathy, persistent ascites, or death excluding nonhepatic causes of these conditions. Competing risk models were used to estimate the annual hazard rate and cumulative incidence of ESLD. Proportional hazards models were used to estimate relative hazards of ESLD with covariates. ESLD developed in 127 of the HCV/HIV-coinfected participants, with an estimated 16-year cumulative incidence of 14.0% (95% confidence interval [CI], 11.6%-16.4%). Without HIV, 10 HCV-infected participants developed ESLD, for a significantly lower cumulative incidence of 2.6% (95% CI, 1.0%-4.3%, P <.0001). ESLD risk increased steeply with age in both groups. With HIV, ESLD risk was increased 8.1-fold (95% CI, 1.9-35.2) with HBV surface antigenemia, 2.1-fold (95% CI, 1.3-3.3) with fewer than 0.2 x 10(9)/L (200/microL) CD4(+) lymphocytes, and 1.04-fold (95% CI, 1.03-1.06) per year of age. Thus, HIV is associated with a markedly increased risk of HCV-related ESLD for persons with hemophilia, particularly with HBV infection, low CD4(+) lymphocytes, or older age.

The North American Immune Tolerance Registry was initiated to study of immune tolerance (ITT) in Canada and the United States with respect to: 1) therapeutic regimens in use for haemophilia A (HA) and B (HB) inhibitor patients; 2) therapeutic outcomes; 3) potential predictors of successful outcome and 4) complications of therapy. Data on 188 ITT courses was collected by questionnaire from 60 haemophilia centers from 1993-99. Among the completed courses, the overall success rate was 70% (115/164) for all HA and 31% (5/16) for all HB. Outcome parameters noted to be predictive of ITT success for all HA were 1) pre-ITT induction (p = 0.003), 2) ITT peak (p = 0.007) and 3) historical pre ITT peak (p = 0.04) inhibitor titres. An inverse correlation between total daily dose (units/kg/day) and success: (80% with under 50; 71% with 50-99; 73% with 100-199; and 41% with > or = 200, p = 0.01) was found. Outcome predictors were not evaluable for HB, although adverse reactions to therapy, including nephrotic syndrome, and access complications were more common among failed courses. Infection most often complicated the use of access catheters. These results are discussed within the context of the international ITT registry and upcoming prospective ITT study.

The issue of factors predisposing for inhibitor development in haemophilia patients is still largely unresolved. In an attempt to address this problem, we initiated a registry in 1996 of siblings with haemophilia and with or without a history of inhibitors. Four hundred and sixty families have accrued, of whom 388 suffer from haemophilia A and 72 haemophilia B. Twenty-five of the brother pairs are twins. The inhibitor incidence in all families with severe haemophilia A was 31.7%. The corresponding figure in the caucasian patients was 27.4%, whereas a higher incidence of inhibitors was reported in the black subjects (55.6%). Twins were reported in six of the 100 inhibitor families, for whom monozygocity was confirmed in three cases. In 32 families (32%), at least two brothers had a history of inhibitors. In 22 (69%) of these families, the inhibitor was also of the same type, i.e. either high- or low-responding. The overall concordance within the severe haemophilia A families was found to be 78.3% (195/249) compared to an expected figure of 68.0% and 58.0% using an inhibitor incidence of 20 and 30%, respectively (P < 0.0001). The corresponding figure for the twins was 88.2% (15/17). Moreover, the risk for inhibitor development in families with a previous inhibitor history was found to be 48% (95% confidence interval [CI] 35-62%), whereas the risk in families with no previous known inhibitor was only 15% (95% CI 11-21%) corresponding to a relative risk of 3.2 (95% CI 2.1-4.9). Immune-tolerance induction was reported in 24 families, of whom 13 siblings were successfully treated. Our data clearly support the concept that a genetic predisposition for inhibitor development exists. However, the markers of this predisposition remain to be elucidated and we believe that the MIBS registry will be useful for this purpose.

Two immune tolerance registries--the International Immune Tolerance Study Group (ITSG) and North American Immune Tolerance Study (NAITS) - are compared and findings from combined data reported. The registries differed with respect to data collection tools, location, host and environmental factors, start date distribution and treatment products. The success and failure rates were similar in the two studies. There was a highly significant association between maximum historical titre and immune tolerance success; the success rate decreased as the historical titre increased. There was a significant association between inhibitor titre immediately prior to treatment and the probability for treatment success, and between outcome and time from diagnosis to treatment in the ITSG (of borderline significance in the NAITS). There was a significant association between outcome and dose, though the direction of the associations was not the same. In the ITSG, success was associated with doses greater than or equal to 200 IU/kg/day, while in the NAITS, greater success was observed with doses of less than 50 IU/kg/day. There was no association between outcome and treatment product. Data from the two registries were combined to produce a table for calculating the chance of successful treatment by historical titre, pretreatment titre, and dose.

Objective: To determine if the long-term incidence of the acquired immunodeficiency syndrome (AIDS) is related to human immunodeficiency virus type 1 (HIV-1) RNA levels measured early in HIV-1 infection., Design: Epidemiologic cohort study., Setting: Five hemophilia treatment centers in the United States., Subjects: A total of 165 subjects with hemophilia and HIV-1 infection (age at HIV-1 seroconversion, 1-66 years) followed from 1979 to 1995., Methods: The HIV-1 RNA level was measured by polymerase chain reaction over a range of 200 to 1 million or more HIV-1 RNA copies/mL in archived serum specimens collected 12 to 36 months (median, 27 months) after the estimated date of HIV-1 seroconversion. Kaplan-Meier methods were used to examine the risk of AIDS and proportional hazards models were used to estimate relative hazards., Results: The HIV-1 RNA values were similar in subjects younger than 17 years at seroconversion (median, 5214 copies/mL) and those 18 to 34 years old (median, 4693 copies/mL), but higher in those 35 years or older (median, 12069 copies/mL) (P = .02 compared with each younger group). At 10 years after seroconversion, the proportions of subjects with AIDS were 72% among subjects with 100,000 or more HIV-1 RNA copies/mL measured 12 to 36 months after HIV-1 seroconversion (n = 9), 52% among subjects with 10,000 to 99,999 copies/mL (n = 55), 22% among subjects with 1000 to 9,999 copies/mL (n = 82), and 0% among subjects with fewer than 1000 copies/mL (n = 19) (P < .001). The age-adjusted relative hazard for AIDS for subjects with 10,000 or more copies/mL was 14.3 (95% confidence interval, 1.9-105.6) compared with subjects with fewer than 1000 copies/mL., Conclusions: The HIV-1 RNA level during early chronic HIV-1 infection is a strong, age-independent predictor of clinical outcome; low levels define persons with a high probability of long-term AIDS-free survival.

Blood samples were obtained from 16 hemophiliacs who had a 50%-94% defined risk of human immunodeficiency virus (HIV) type 1 infection on the basis of treatment history and from 14 controls not at risk for HIV infection. HIV-1 was not detected in any of 12 patient samples by cocultivation nor in 14 patient samples by the polymerase chain reaction. Peripheral blood cells from 7 seronegative hemophiliacs at highest risk of seroconversion (94%) were less susceptible to HIV-1 infection in vitro than were cells from healthy controls (P < .025, one-tailed Wilcoxon rank sum test). In contrast, the susceptibility to HIV-1 infection of lymphocytes from 6 seronegative hemophiliacs at moderate risk (50%-56%) of seroconversion did not differ from that of cells from controls or from high-risk hemophiliacs. Therefore, prolonged periods of seronegative HIV-1 infection are not common in this high-risk population. In addition, among hemophiliacs there may exist heterogeneity in susceptibility to HIV-1 infection in vitro and in vivo.

Objective: To assess the association between human leukocyte antigen (HLA) haplotypes and the incidence rates of CD4 decline to < 20% and to AIDS., Design: Retrospective cohort study of 95 HIV-1-infected hemophilic sibling pairs., Methods: HLA haplotype-sharing between siblings was assigned on the basis of serologic typing of HLA class I alleles and molecular typing of HLA class II alleles. Concordance of time to CD4 decline to < 20% and to AIDS within and between sibling pairs was assessed by analysis of variance models and calculations of intraclass correlation coefficients. The age-adjusted relative risks of these two endpoints for unique class II haplotypes were determined from proportional hazards models., Results: Sibling pairs sharing one or two haplotypes were significantly concordant in CD4 decline and AIDS status within 5 years of seroconversion. No concordance was found in pairs sharing zero haplotypes. At 6-10 years after seroconversion, significant concordance of these two endpoints was also observed in the pairs sharing one haplotype. The concordant results were not explained by the use of zidovudine within the pairs. Among the individuals in this cohort, the relative hazards for CD4 decline to < 20% and for AIDS were significantly elevated for one class II haplotype (DQB1*0501, DQA1*0101, DRB1*0101). In addition, the risk for AIDS was significantly increased for two other class II haplotypes (DQB1*0603, DQA1*0103, DRB1*1300, DRB3*0202 and DQB1*0301, DQA1*0501, DRB1*1400, DRB3*0202) and significantly decreased for one haplotype (DQB1*0302, DQA1*0301, DRB1*0401, DRB4*0101)., Conclusions: These data demonstrate that HIV-1 disease progression is associated with the genes in the major histocompatibility complex that regulate the host's immune response.

We studied human immunodeficiency virus type 1 (HIV-1) infection incidence over time in a 16-center cohort of hemophiliacs in the United States and Europe and estimated the most likely date of seroconversion for all seropositive subjects. Five U.S. centers enrolled subjects independent of HIV-1 status, whereas 11 centers preferentially included seropositive subjects. We obtained unbiased estimates of HIV-1 infection incidence rates from the five centers and estimated dates of seroconversion from the distribution seen among seropositives from all centers. In the five-center cohort, infection incidence began in 1978, peaked in October 1982 at 22 infections per 100 person-years at risk, and declined to 4 per 100 person-years by July 1984. Few infections occurred after 1987, and by that time, 50% of the cohort had become infected. Median seroconversion dates for subgroups of all seropositives ranged from July 1980 to December 1983, depending on the dose and type of factor concentrate. Median dates in Europe ranged from September 1981 to March 1983 and reflected the use of products manufactured from American plasma. Infection incidence apparently peaked about the same time that public health interventions were introduced to reduce transmission. These interventions, including heat treatment of factor concentrates and deferral of high-risk donors, have prevented HIV-1 infection from becoming endemic among younger birth cohorts of persons with hemophilia.

To evaluate the effects of human immunodeficiency virus type 1 (HIV-1) infection on the loss of factor VIII alloantibodies, we identified 77 patients with a history of inhibitors from among a large cohort of HIV-1-infected participants enrolled in a natural history study of HIV-1 infection in hemophilia. Fifty-six patients were high responders with inhibitors titers greater than 5 Bethesda Units (BU) measured on at least one occasion. From May 1985 to December 1989, 13 of the high-responder patients were rechallenged with factor VIII concentrates after several years of treatment with other plasma products. All exhibited excellent hemostasis upon reinstitution of factor VIII. Seven of the 13 patients (11.3-46.3 years of age) were in the advanced stages of HIV-1 infection at the time of rechallenge. Inhibitor titers measured subsequent to the reinstitution of factor VIII were consistently less than 1 BU in five of these seven patients. The remaining six patients (6.1-57.5 years of age) had mild to moderate CD4+ lymphocyte depletion (absolute CD4+ cells: 262-935/mm3) at the time of factor VIII rechallenge. Follow-up inhibitor titers were negative 7-42 months after consistent factor VIII use in these six patients. The lack of anamnestic response to factor VIII in all 13 patients who were rechallenged indicates that HIV-1-infected patients who have a history of high-responder inhibitors frequently benefit from the reintroduction of factor VIII use for the control of bleeding, regardless of their stage of HIV-1 disease.